NKG2D and Related Immunoreceptors

Adv Protein Chem. 2004;68:281-312. doi: 10.1016/S0065-3233(04)68008-9.


NK cells are crucial components of the innate immune system, capable of directly eliminating infected or tumorigenic cells and regulating down-stream adaptive immune responses. Unlike T cells, where the key recognition event driving activation is mediated by the unique T cell receptor (TCR) expressed on a given cell, NK cells express multiple activating and inhibitory cell-surface receptors (NKRs), often with overlapping ligand specificities. NKRs display two ectodomain structural homologies, either immunoglobulin- or C-type lectin-like (CTLD). The CTLD immunoreceptor NKG2D is found on NK cells but is also widely expressed on T cells and other immune system cells, providing stimulatory or co-stimulatory signals. NKG2D drives target cell killing following engagement of diverse, conditionally expressed MHC class I-like protein ligands whose expression can signal cellular distress due to infection or transformation. The symmetric, homodimeric receptor interacts with its asymmetric, monomeric ligands in similar 2:1 complexes, with an equivalent surface on each NKG2D monomer binding extensively and intimately to distinct, structurally divergent surfaces on the ligands. Thus, NKG2D ligand-binding site recognition is highly degenerate, further demonstrated by NKG2D's ability to simultaneously accommodate multiple non-conservative allelic or isoform substitutions in the ligands. In TCRs, "induced-fit" recognition explains cross-reactivity, but structural, computational, thermodynamic and kinetic analyses of multiple NKG2D-ligand pairs show that rather than classical "induced-fit" binding, NKG2D degeneracy is achieved using distinct interaction mechanisms at each rigid interface: recognition degeneracy by "rigid adaptation." While likely forming similar complexes with their ligand (HLA-E), other NKG2x NKR family members do not require such recognition degeneracy.

Publication types

  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Killer Cells, Natural / immunology
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • NK Cell Lectin-Like Receptor Subfamily K
  • Phylogeny
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology*
  • Receptors, Immunologic / metabolism
  • Receptors, Natural Killer Cell
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship


  • Histocompatibility Antigens Class I
  • KLRK1 protein, human
  • Ligands
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Antigen, T-Cell
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell